cibisatamab (RG7802)

P1, N=47, Terminated, Hoffmann-La Roche | Completed --> Terminated; The Sponsor terminated the study because development of cibisatamab has been discontinued.

P1/2, N=675, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Jun 2026 --> Sep 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2027 --> Nov 2026

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC.

P1, N=47, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=80, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Jul 2025 --> Dec 2024 | Trial primary completion date: Jul 2025 --> Dec 2024

P1/2, N=675, Recruiting, Hoffmann-La Roche | N=470 --> 675 | Trial completion date: Nov 2026 --> Sep 2027 | Trial primary completion date: Aug 2025 --> Jun 2026

P1/2, N=80, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. Depending on the dosing schedule and FAP-4-1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose-response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection.

P1, N=47, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Oct 2023 --> Mar 2024 | Trial primary completion date: Oct 2023 --> Mar 2024

P1/2, N=470, Recruiting, Hoffmann-La Roche | Trial completion date: Aug 2025 --> Nov 2026 | Trial primary completion date: Apr 2024 --> Aug 2025

We generated a virtual patient cohort with the model to conduct in silico virtual clinical trials for combination therapy of a PD-L1 checkpoint inhibitor (atezolizumab) and a bispecific T cell engager (cibisatamab). Using the model calibrated against the clinical trials, we conducted several virtual clinical trials to compare various doses and schedules of administration for two drugs with the goal of therapy optimization. Moreover, we quantified the score of drug synergy for these two drugs to further study the role of the combination therapy.

P1, N=47, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2022 --> Sep 2023 | Trial primary completion date: Dec 2022 --> Sep 2023

P1/2, N=80, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2024 --> Jul 2025 | Trial primary completion date: Oct 2024 --> Jul 2025

Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials...Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.

Immunotherapies targeting CEACAM have achieved some clinical benefit, e.g. Tusamitamab Ravtansine (anti-CEACAM5 ADC), that has shown decent disease control in NSCLC...For instance, Cibisatamab, targeting CEACAM5 and CD3, is currently under clinical investigation in CRC patients... In summary, a bispecific TCE with high selectivity to CEACAM5/6 overexpressing cancer cells was engineered. It displays potent anti-tumor efficacy, and support from target selectivity testing shows promising safety traits.

P1, N=46, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Feb 2022 --> Oct 2022 | Trial primary completion date: Feb 2022 --> Oct 2022

P1/2, N=435, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2023 --> Aug 2025 | Trial primary completion date: Feb 2022 --> Apr 2024

P1/2; N=435; Recruiting; Sponsor: Hoffmann-La Roche; Trial primary completion date: Jun 2022 --> Feb 2022

P1/2, N=435, Recruiting, Hoffmann-La Roche | Trial completion date: Feb 2024 --> Nov 2023

P1/2, N=80, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2024 --> Oct 2024 | Initiation date: Apr 2021 --> Jul 2021 | Trial primary completion date: Jun 2024 --> Oct 2024

P1/2, N=435, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2023 --> Feb 2024 | Trial primary completion date: Feb 2022 --> Jun 2022

P1/2, N=80, Recruiting, Hoffmann-La Roche

P1/2, N=380, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2022 --> Nov 2023

The ability of this tracer to quantify CD8 T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL...Taken together, the anti-CD8-minibody 89Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8+ T cell infiltrates upon either single or combination treatment with T cell bispecific antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in Clinical Phase II, is a promising monitoring tool for intratumoral CD8+ T cells in patients treated with CIT.

Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8 T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.

P1; Recruiting --> Active, not recruiting

P1, N=228, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1, N=149, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2; N=410 --> 250

P1; Not yet recruiting --> Recruiting

P1; N=46; Not yet recruiting; Sponsor:Hoffmann-La Roche

P1/2; N=292 --> 410

P1, N=228, Active, not recruiting, Hoffmann-La Roche | N=410 --> 228 | Trial completion date: Jul 2019 --> Dec 2019 | Trial primary completion date: Apr 2019 --> Dec 2019

P1, N=149, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Aug 2019 --> Apr 2019 | Trial primary completion date: Aug 2019 --> Apr 2019

P1, N=410, Active, not recruiting, Hoffmann-La Roche | N=226 --> 410

P1, N=226, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=410 --> 226

P1, N=410, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1, N=185, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Apr 2018 --> Aug 2019 | Trial primary completion date: Apr 2018 --> Aug 2019

P1, N=410, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting